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DC Field | Value | Language |
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dc.contributor.advisor | García Ruiz, María del Carmen | - |
dc.contributor.advisor | Fernández-Checa Torres, José Carlos | - |
dc.contributor.author | Solsona i Vilarrasa, Estel | - |
dc.contributor.other | Universitat de Barcelona. Departament de Biomedicina | - |
dc.date.accessioned | 2023-04-25T09:46:35Z | - |
dc.date.available | 2023-04-25T09:46:35Z | - |
dc.date.issued | 2021-03-22 | - |
dc.identifier.uri | http://hdl.handle.net/2445/197202 | - |
dc.description.abstract | [eng] Cholesterol accumulation in mitochondrial membranes is a common feature of various chronic diseases, such as cardiovascular disease, cancer, and Alzheimer's as well as liver diseases. Studies prior to this doctoral thesis have shown that the increase in mitochondrial cholesterol (mChol) alters the physical properties of mitochondrial membranes and negatively impacts the organelle function. These intracellular changes in turn initiate a sequence of pathological processes that end up resulting in cell and tissue damage. Based on these data, the main objective of this doctoral thesis has been to identify new effects that mChol accumulation produces on liver mitochondrial functionality. Likewise, we have also wanted to characterize the pathological mechanisms associated with the accumulation of mChol in two hepatic diseases: alcoholic liver disease and Niemann-Pick type C disease (NPC). To address these objectives, the following studies have been carried out. Study 1) Characterization of mChol accumulation effects on functionality of mitochondria in liver tissue. Previous studies have shown that the accumulation of mChol increases the rigidity of mitochondrial membranes and prevents the import of the antioxidant glutathione (GSH), thus causing mitochondrial dysfunction. The results of this thesis show new mechanisms associated with the increase in mChol, including an increase in the cholesterol transporters to mitochondria StARD1 and MLN64, and an alteration in mitochondrial morphology. In addition, it has been shown that cholesterol enrichment also decreases membrane potential and mitochondrial respiration, while altering the assembly of respiratory supercomplexes. This mChol accumulation causes liver damage, reflected by an increase in oxidative stress, a decrease in mGSH, and an increase in transaminase levels. This liver damage, as well as the other previously mentioned parameters, can be reversed with the use of glutathione ester, a compound that increases the levels of mGSH. Study 2) Identification of the effects of alcohol consumption on the levels of mChol and its transporter StARD1 throughout the liver acinus. In recent decades, several molecules and signaling pathways involved in the pathology of alcoholic liver disease have been described. Among them, it has been observed that the accumulation of mChol induces GSH depletion and an increase in oxidative stress, resulting in liver damage. In this thesis, StARD1 has been characterized as the main regulator of mChol accumulation in alcoholic liver disease. Alcohol consumption has been shown to increase the expression of StARD1 specifically in the perivenous areas of the liver. In this same region, the greatest accumulation of mChol, GSH depletion and increased oxidative stress are observed. Additionally, it has been observed that alcohol consumption dramatically affects the mitochondrial morphology of hepatocytes from the perivenous area compared to the periportal ones. It has been shown that the role of StARD1 is relevant in this mechanism, since its absence in mice deficient in StARD1 interrupts the accumulation of mChol in perivenous hepatocytes after alcohol intake, as well as the consequent increase in oxidative stress and liver damage. Study 3) Investigation of the role of StARD1 in the mechanisms associated with mChol accumulation in Niemann-Pick type C disease. mChol accumulation is a hallmark of NPC disease, causing mitochondrial dysfunction and depletion of antioxidant defenses. Following these previous data, the results of this thesis connect the increase in mChol in NPC with an increase in StARD1 and a deficiency of acid ceramidase. It has been observed that while mChol and StARD1 levels are increased in NPCs, those of acid ceramidase are decreased. Significantly, and as a possible mechanism for reversing the NPC phenotype, it has been observed that overexpression of acid ceramidase induces a reduction in StARD1 and mChol levels, as well as an improvement in the mitochondrial and cellular functionality of NPC fibroblasts. As a summary, this doctoral thesis describes new effects that mChol accumulation produces on liver mitochondrial functionality as well as reveals new pathological mechanisms associated with alcoholic liver disease and NPC disease, findings that may provide new treatment opportunities for both diseases. | ca |
dc.description.abstract | [cat] L'acumulació de colesterol a les membranes mitocondrials és una característica comuna de diferents malalties cròniques, com malalties cardiovasculars, càncer i Alzheimer a més de malalties hepàtiques. Estudis previs a aquesta tesi doctoral han demostrat que l'augment de colesterol mitocondrial (mCol) altera les propietats físiques de les membranes mitocondrials i impacta negativament en la funció de l'orgànul. Aquests canvis intracel·lulars inicien alhora una seqüència de processos patològics que acaben resultant en dany cel·lular i tissular. Considerant aquestes dades, l'objectiu principal d'aquesta tesi doctoral ha estat identificar nous efectes que l'acumulació de mCol produeix en la funcionalitat mitocondrial hepàtica. També s'han volgut caracteritzar els mecanismes patològics associats a l'acumulació de mCol en dues malalties hepàtiques: l'hepatopatia alcohòlica i la malaltia de Niemann- Pick tipus C (NPC). Aquesta tesi descriu nous mecanismes associats a l'increment de mCol que causen dany hepàtic: augment del transportador de mCol StARD1, alteració de la morfologia i respiració mitocondrial, i pertorbació de l'acoblament dels supercomplexos respiratoris. Aquestes observacions són rellevants per entendre les conseqüències de l'enriquiment de mCol en el context de la malaltia hepàtica i es podrien investigar en altres malalties cròniques que també presenten aquest fenotip. Considerant la importància de l'acumulació de mCol a l'hepatopatia alcohòlica i la malaltia de NPC, els resultats d'aquesta tesi revelen un nou mecanisme patològic comú que involucra StARD1. La inducció de StARD1, l'enriquiment de mCol i l'esgotament del glutatió mitocondrial són responsables de la disfunció mitocondrial i l'estrès oxidatiu subjacent en el fenotip d'ambdues malalties, alteracions que es podrien explorar per al desenvolupament de teràpies potencials per a aquestes patologies. | ca |
dc.description.abstract | [spa] La acumulación de colesterol en las membranas mitocondriales es una característica común de distintas enfermedades crónicas, como enfermedades cardiovasculares, cáncer y Alzheimer además de enfermedades hepáticas. Estudios previos a la presente tesis doctoral han demostrado que el aumento de colesterol mitocondrial (mCol) altera las propiedades físicas de las membranas mitocondriales e impacta negativamente en la función del orgánulo. Estos cambios intracelulares inician a su vez una secuencia de procesos patológicos que terminan resultando en daño celular y tisular. En base a estos datos, el objetivo principal de esta tesis doctoral ha sido identificar nuevos efectos que la acumulación de mCol produce en la funcionalidad mitocondrial hepática. Así mismo, también se han querido caracterizar los mecanismos patológicos asociados a la acumulación de mCol en dos enfermedades hepáticas: la hepatopatía alcohólica y la enfermedad de Niemann-Pick tipo C (NPC). La presente tesis describe nuevos mecanismos asociados al incremento de mCol que causan daño hepático: aumento del transportador de mCol StARD1, alteración de la morfología y respiración mitocondrial, y perturbación del ensamblaje de los supercomplejos respiratorios. Estas observaciones son relevantes para entender las consecuencias del enriquecimiento de mCol en el contexto de la enfermedad hepática y podrían investigarse en otras enfermedades crónicas que también presentan este fenotipo. Considerando la importancia de la acumulación de mCol en la hepatopatía alcohólica y la enfermedad de NPC, los resultados de esta tesis revelan un nuevo mecanismo patológico común que involucra StARD1. La inducción de StARD1, el enriquecimiento de mCol y el agotamiento del glutatión mitocondrial son responsables de la disfunción mitocondrial y el estrés oxidativo que subyace en el fenotipo de ambas enfermedades, alteraciones que se podrían explorar para el desarrollo de terapias potenciales para estas patologías. | ca |
dc.format.extent | 208 p. | - |
dc.format.mimetype | application/pdf | - |
dc.language.iso | eng | ca |
dc.publisher | Universitat de Barcelona | - |
dc.rights | (c) Solsona i Vilarrasa, Estel, 2023 | - |
dc.source | Tesis Doctorals - Departament - Biomedicina | - |
dc.subject.classification | Malalties del fetge | - |
dc.subject.classification | Hepatopaties alcohòliques | - |
dc.subject.classification | Mitocondris | - |
dc.subject.classification | Colesterol | - |
dc.subject.classification | Malalties de Niemann-Pick | - |
dc.subject.other | Liver diseases | - |
dc.subject.other | Alcoholic liver diseases | - |
dc.subject.other | Mitochondria | - |
dc.subject.other | Cholesterol | - |
dc.subject.other | Niemann-Pick diseases | - |
dc.title | Cholesterol and StARD1: a common nexus in Alcoholic Liver Injury and Niemann-Pick Type C disease-associated mitochondrial stress | ca |
dc.type | info:eu-repo/semantics/doctoralThesis | ca |
dc.type | info:eu-repo/semantics/publishedVersion | - |
dc.rights.accessRights | info:eu-repo/semantics/openAccess | ca |
dc.identifier.tdx | http://hdl.handle.net/10803/688149 | - |
Appears in Collections: | Tesis Doctorals - Departament - Biomedicina |
Files in This Item:
File | Description | Size | Format | |
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ESV_PhD_THESIS.pdf | 15.09 MB | Adobe PDF | View/Open |
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